2. Academic Validation
  3. Cell-Based Progression of Spiroindoline Phenotypic Hits Leads to the Identification of Compounds with Diverging Parasitological Profiles against the Human Malaria Parasite Plasmodium falciparum

Cell-Based Progression of Spiroindoline Phenotypic Hits Leads to the Identification of Compounds with Diverging Parasitological Profiles against the Human Malaria Parasite Plasmodium falciparum

  • J Med Chem. 2025 May 22;68(10):10156-10172. doi: 10.1021/acs.jmedchem.5c00302.
Jean Dam 1,  Grant A Boyle 1,  André Horatscheck 1,  John G Woodland 1 2,  Claire Le Manach 1,  Gurminder Kaur 1,  Dale Taylor 1,  Liezl Krugmann 1,  Mathew Njoroge 1,  Nina Lawrence 1,  Christel Brunschwig 1,  Victor Zdorichenko 3,  Brian Cox 3,  Sergio Wittlin 4 5,  Thomas W von Geldern 6,  Dennis Smith 6,  James Duffy 6,  Gregory S Basarab 1,  Kelly Chibale 1 7 2
Affiliations

Affiliations

  • 1 Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch 7701, South Africa.
  • 2 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
  • 3 Department of Chemistry, Arundel Building 305. School of Life Sciences, University of Sussex, Falmer, Brighton, Sussex BN1 9RH, United Kingdom.
  • 4 Swiss Tropical and Public Health Institute, Kreuzstrasse 2, Allschwil 4106, Switzerland.
  • 5 University of Basel, Basel4002, Switzerland.
  • 6 Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, PO Box 1826, Geneva 1215, Switzerland.
  • 7 South African Medical Research Council Drug Discovery and Development Research Unit, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa.
PMID: 40353796 DOI: 10.1021/acs.jmedchem.5c00302
Abstract

In the search for novel chemotypes with high sp3 character and activity against the human malaria Parasite Plasmodium falciparum, a spiroindoline series was identified from a phenotypic high-throughput screening campaign. The spiroindoline hit 2 displayed good activity against both drug-sensitive and multidrug-resistant Plasmodium strains, making it an attractive starting point for hit-to-lead progression. Structure-activity relationship studies led to the identification of a novel pyridylspiroindoline frontrunner (50) with improved antiplasmodial activity, aqueous solubility, and microsomal metabolic stability. Data from additional parasitological profiling suggested that 50 likely has a mode of action differing from that of the original spiroindoline hit. Compound 50 showed excellent in vivo pharmacokinetics with efficacy being achieved in a humanized immunodeficient NSG mouse P. falciparum Infection model. This provided a pharmacological proof-of-concept for this series, making it a valuable starting point for further optimization in the quest for novel antimalarial therapeutics.

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